Divergent Synthesis of Methylisatoid and Tryptanthrin Derivatives by Ph3P-I2-Mediated Reaction of Isatins with and without Alcohols

Article abstract of DOI:10.1021/acs.joc.0c02403

A novel phosphonium-mediated reaction of isatins is described. In the presence of alcohol, the reaction proceeds to furnish C-12 modified tryptanthrin derivatives. Without alcohol, self-dimerization of isatins gives rise to tryptanthrin and its analogs. T

Full text of DOI:10.1021/acs.joc.0c02403

pubs.acs.org/joc
Note
Divergent Synthesis of Methylisatoid and Tryptanthrin Derivatives
by Ph3P−I2‑Mediated Reaction of Isatins with and without Alcohols
Mookda Pattarawarapan, Nittaya Wiriya, Surat Hongsibsong, and Wong Phakhodee*
Cite This: https://dx.doi.org/10.1021/acs.joc.0c02403
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A novel phosphonium-mediated reaction of isatins
is described. In the presence of alcohol, the reaction proceeds to
furnish C-12 modified tryptanthrin derivatives. Without alcohol,
self-dimerization of isatins gives rise to tryptanthrin and its analogs.
This divergent and step-economic approach provides a facile
access to diverse indoloquinazoline structures including the natural alkaloids, methylisatoid and cephalanthrin B, in high yields from
simple precursors under mild and metal-free reaction conditions.
ryptanthrin and the related derivatives such as phaitan-
with different aryl substituents include condensation of isatins
with isatoic anhydrides,15 oxidative cyclization of isatoic
anhydrides and 2-aminoacetophenones,16 photochemical re-
action of indoles with anthranilic acids,17 and copper-catalyzed
reaction of isatins with indoles.18
T
thrins A−E,1a cephalanthrin A,1b methylisatoid,1a−c and
cephalanthrin B1b are naturally occurring indolo[2,1-b]-
quinazoline alkaloids which have been isolated from various
plant sources as well as different cell cultures (Figure 1).1d
Synthesis of other structurally more diverse indoloquinazo-
lines is considered a challenging task which often requires
multistep synthesis or the use of complicated substrates. While
a number of methods have been introduced for C-6
functionalization of tryptanthrins,19 modification at the C-12
position remains largely unexplored.20 Considering these facts
and in continuation of our interest in the Ph3P−I2-mediated
reactions,21 herein, we disclose a novel methodology for the
divergent synthesis of methylisatoid and tryptanthrin deriva-
tives (2 and 3, respectively) from isatins 1 in the presence and
in the absence of alcohols as depicted in Scheme 1.
Our initial investigation involved the reaction between isatin
(1a) and methanol using the combination of Ph3P−I2 as an
activator in the presence of the triethylamine base. To our
surprise, when using a 1:1 mol ratio of 1a and methanol,
instead of the expected O-methylisatin A (Z = H, R = Me),
compound 2a was isolated in 83% yield. Based on
spectroscopic analysis, its structure was identified as 12-
hydroxy-12-methoxycarbonyltryptanthrin which is known as
methylisatoid.1 Since O-alkylated isatins are highly unstable,22
O-methylated product, if formed, may undergo rapid
condensation with another isatin molecule to yield 2. Due to
nucleophilicity of the isatin nitrogen, formation of 2 through
Figure 1. Indoloquinazolines isolated from natural sources.
These compounds have attracted considerable interest as
potential therapeutic agents mainly due to their broad
spectrum of biological and pharmaceutical activities.2 Some
of them include antitumor,3 antiparasitic,4 antimicrobial,5 anti-
inflammatory,6 antimalarial,7 antiviral,8 and antitubercular9
properties.
Owning to their promising benefits, a number of synthetic
approaches have been developed to gain access to these core
structures.10 One of the most straightforward methods toward
tryptanthrins is through self-dimerization of isatins. Different
reaction conditions have been applied including visible-light
mediated photoredox catalysis,11 cathodic reduction,12 POCl3-
mediated reaction,13 and oxidative cyclization using I2,14a,b
KMnO4,14c or tBuO2H14d as an oxidant. Some recent examples
of alternative protocols to install the tryptanthrin framework
Received: October 10, 2020
https://dx.doi.org/10.1021/acs.joc.0c02403
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Scheme 1. Divergent Synthesis of Methylisatoid and Tryptanthrin Derivatives
a
Scheme 2. Synthesis of Methylisatoid Derivatives
a
b
Reaction conditions: 1 (0.68 mmol), PPh3 (0.51 mmol), I2 (0.51 mmol), alcohol (0.51 mmol), Et3N (1.70 mmol), CH2Cl2 (5 mL). Reaction
performed in gram scale using 1a (10 mmol).
initial condensation of two molecules of 1a before reacting
with the alcohol is also a possible alternative.
chlorosuccinimide, N-bromosuccinimide, and N-iodosuccini-
mide led to recovery of unreacted isatin.
Without further optimization of the reaction conditions, the
scope and generality of the reaction were then examined with
different isatins and alcohols. To determine the scope with
regard to the nature of isatin precursors (see Figure S1),
methanol was applied as a common nucleophile leading to aryl
substituted methylisatoid derivatives. According to Scheme 2,
both electronic and steric factors have strong influence on the
outcome of the reaction. Isatins with electron-donating group
(−Me, −OMe) on the C5, para to the nitrogen atom, reacted
rapidly to provide the corresponding methyl esters 2b and 2c
in high yields, whereas those bearing electron-withdrawing
groups (−Br and −Cl) at the same position gave lower yields
of 2d and 2e with some remaining isatin precursors even after
Based on this rationale, we decided to further investigate the
reaction toward C-12 modified tryptanthrin derivatives 2. By
adjusting the amounts of the substrates (see Table S1), it was
found that using a 2:1.5 mol ratio of 1a and methanol gave the
highest yield of the product 2a (89%). The reaction in the
presence of other organic bases including pyridine, imidazole,
and diisopropylethylamine, however, failed to give 2a as
substantial amounts of starting material still remained. Several
attempts to increase the yield of 2a via extending reaction
times, increasing the temperature, or changing the order of
reagent addition also led to unsatisfactory results, while
replacing I2 with other halogenated additives including N-
B
https://dx.doi.org/10.1021/acs.joc.0c02403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
a
prolonged reaction times (up to 24 h). Owning to the poor
nucleophilicity of the aryl amido group, the electron-deficient
5-nitroisatin did not convert to the expected product 2f.
Likewise, the reaction of hindered 7-methylisatin gave rise to a
complex mixture in which the expected product 2g was not
isolated. Surprisingly, the presence of CF3 on the C4 of isatin
exerts little effect on the yield of 2h.
Scheme 3. Synthesis of Tryptanthrin Derivatives
With the scope of the reaction with respect to the isatin
structure determined, the effect of the type of alcohols on the
formation of 2 was further investigated. As shown in Scheme 2,
compounds 2i and 2j were afforded in high yields from
primary alcohols having different carbon chain lengths. Benzyl
alcohol and its derivatives also provided the corresponding
hydroxy esters 2k−2p in satisfactory yields. Adding an
electron-donating −OMe group to the benzene ring of the
alcohol led to an increased yield of 2l, whereas the presence of
a strong electron-withdrawing nitro group lowered the yield of
2o. Cinnamyl alcohol having an α,β-unsaturated moiety is also
a viable substrate giving the product 2q in moderate yield.
Sterically hindered secondary alcohols such as cyclohexanol
and 2-propanol are well tolerated providing the corresponding
esters 2r and 2s in reasonable yields. However, no reaction
toward 2t was observed when using the bulkier tert-butanol. In
this case, competitive formation of tryptanthrin 3a was clearly
observed.
Nevertheless, other more interesting substrates including 8-
hydroxyquinoline, a metal chelator with antimicrobial prop-
erty,23 eugenol with anticarcinogenic and antitumor actions,24
and bioactive geraniol25 gave rise to the corresponding
products 2u, 2v, and 2w, respectively, in moderate to good
yields. Since drug combination has been proposed as a
promising strategy to overcome monotherapy resistance,26
modification of the tryptanthrin skeleton that would
simultaneously provide two bioactive agents would render a
great opportunity to achieve new potential drugs having
additive and even synergistic properties.
Having successfully prepared methylisatoid derivatives, we
then turned our attention to the reaction in the absence of
alcohols. Based on the above results, formation of tryptanthrin
side product became prominent when poorly nucleophilic
alcohols were used. It is thus envisaged that the same reaction
conditions without alcohol could be applied to synthesize
tryptanthrin derivatives. Indeed, self-dimerization of isatins
took place to afford tryptanthrin 3a and its substituted analogs
3b−3h in various yields (Scheme 3). In accordance with other
studies,13b,14a the reaction is sensitive to both electronic and
steric effects. While the self-condensation process toward 3g is
disfavored due to the presence of sterically hindered methyl
group, electron-rich isatins react preferably to those electron-
deficient substrates and the reaction toward 3f failed when
using the least reactive 5-nitroisatin.
a
Reaction conditions: 1 (0.68 mmol), PPh3 (0.51 mmol), I2 (0.51
b
mmol), Et3N (1.70 mmol), CH2Cl2 (5 mL). Reaction performed in
gram scale using 1a (10 mmol).
Scheme 4. Synthesis of 4 (Cephalanthrin B)
ring-opening of isatins by alcohols could give rise to keto ester
5 which is a known precursor toward 2,20b,c the reaction of
isatin with methanol was examined in the absence of the
Ph3P−I2 system. Based on Scheme 5a, no reaction was
observed suggesting that 5 does not involve in our reaction. It
is also well-known that the Ph3P−I2 reagent is a C−O bond
activator, and the reaction should proceed via an initial
activation of the tautomerizable amide of isatin. Indeed, using
N-methylisatin as the substrate led to no reaction (Scheme
5b). When 2a was subjected to the standard reaction
conditions, only trace amount of 3a was detected (Scheme
5c) indicating that formation of 3a through hydrolysis and
decarboxylation of 2a did not occur. In addition, replacing
methanol with water would theoretically yield the hydrolysate
of methylisatoid. However, possibly due to its high reactivity,
only the decarboxylated product 3a was isolated albeit with
low yield (Scheme 5d).
To demonstrate the synthetic practicality of the reaction,
gram-scale syntheses of methylisatoid (2a) and tryptanthrin
(3a) were carried out using 10 mmol of isatin. The reaction
proceeded smoothly to afford the desired products 2a and 3a
in 75% and 71% yield, respectively. Moreover, with 2a in hand,
we then take this opportunity to synthesize the natural alkaloid
cephalanthrin B (4) which was obtained in high yield through
methylation of 2a with methyl iodide (Scheme 4). Compound
4 showed identical NMR data with the reported literature for
cephalanthrin B which was isolated in racemic form.1b
To better understand the reaction mechanism, control
experiments were carried out as shown in Scheme 5. Since the
It is important to note that, although O-methylisatin (A) has
been applied as a precursor toward methylisatoids,20b,c under
our conditions, no evidence to support its presence could be
found. Moreover, based on the 31P{1H} NMR study (Figure
S2), triphenylphosphine oxide was the only species observed
before adding alcohol, implying a self-dimerized adduct of
isatin as the key intermediate. On the basis of the above
observation and the previously reported literature,13b,20b,c the
mechanism for the formation of 2 and 3 was thus proposed as
depicted in Scheme 6.
The combination of Ph3P with I2 provides reactive
phosphonium species which react with isatin 1 to yield
C
https://dx.doi.org/10.1021/acs.joc.0c02403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Scheme 5. Control Experiments
Scheme 6. Proposed Mechanism
intermediate I. Substitution with the amide NH of another
molecule of isatin provides the dimerized adduct II. An alcohol
attack at the lactam carbonyl of II produces the ring-opening
intermediate III which upon further cyclization gives rise to
the hydroxy ester 2. In the absence of alcohol, II reacts with
water, possibly from moist air, to yield IV. Oxidative
decarboxylation of the cyclized intermediate V then furnishes
tryptanthrin 3.
In summary, this work represents the first concise and
efficient synthesis of C12-modified tryptanthrin analogs using
cheap and readily available isatins as precursors. This divergent
approach not only provides an alternative route toward
tryptanthrin framework but also enables a facile one-pot
synthesis of methylisatoid and the hydroxy ester derivatives in
good yields under mild conditions. Its broad substrate scope,
operational simplicity, and easy scale-up make the protocol
potentially useful for construction of novel indoloquinazoline
derivatives inaccessible by the currently available methods.
EXPERIMENTAL SECTION
■
General Information. All reagents including isatins 1a-1f were
purchased from Sigma-Aldrich or TCI and used without further
purification. Compounds 1g27a and 1h27b were synthesized according
to the reported procedures. All reactions were run in flame- or oven-
dried glassware under N2 gas. The reaction was monitored by thin-
layer chromatography carried out on silica gel plates (60F254
,
MERCK, Germany) and visualized under UV light (254 nm).
Column chromatography was performed over silica gel 60 (70−230
mesh, MERCK, Germany). Melting points were determined using
Mettler Toledo DSC equipment at a heating rate of 6 °C/min and are
uncorrected. NMR spectra were recorded using a Bruker AVANCE
1
(400 and 500 MHz for H). Chemical shifts were reported in parts
per million (ppm, δ) downfield from tetramethylsilane (TMS).
Splitting patterns are described as singlet (s), doublet (d), triplet (t),
quartet (q), quintet (qui), sextet (sex), septet (sep), multiplet (m),
broad (br), doublet of doublets (dd), triplet of doublets (td), and
doublet of doublet of doublets (ddd). High-resolution mass spectra
D
https://dx.doi.org/10.1021/acs.joc.0c02403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(HRMS) were recorded using the Agilent 6546 LC/Q-TOF via the
electrospray ionization (ESI).
Methyl 12-Hydroxy-6-oxo-3,9-bis(trifluoromethyl)-6,12-dihydro-
indolo[2,1-b]quinazoline-12-carboxylate (Scheme 2, 2h). Yellow
solid (0.0951 g, 63% yield); mp 230−231 °C; Rf 0.32 (30% EtOAc/
General Procedure for the Synthesis of Methylisatoid Derivatives
2. To a solution of iodine (129 mg, 0.51 mmol) and
triphenylphosphine (134 mg, 0.51 mmol) in freshly distilled
dichloromethane (5 mL) were added isatins (0.68 mmol) at 0 °C
under N2. After addition of triethylamine (0.24 mL, 1.70 mmol) and
stirring for 10 min, alcohol (0.51 mmol) was added, followed by
warming up to room temperature with continuous stirring. After
completion of the reaction, the crude mixture was concentrated under
reduced pressure before purification by column chromatography
(CC) using ethyl acetate/hexanes as the eluent.
Gram scale synthesis of 2a was carried out as described above using
1a (1.47 g, 10 mmol), iodine (1.9 g, 7.5 mmol), triphenylphosphine
(1.97 g, 7.5 mmol), methanol (0.30 mL, 7.5 mmol), and triethylamine
(3.5 mL, 25 mmol) in freshly distilled dichloromethane (50 mL) to
provide 2a in 1.16 g (75%).
1
hexanes); H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 1H),
7.82 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 8.0 Hz,
1H), 7.59 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 5.39 (s, 1H),
3.73 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 179.6, 167.8,
3
149.8, 142.1, 142.0, 137.2, 134.1, 130.9, 128.7 (q, JCF = 6.25 Hz),
1
128.0 ((q, 2JCF = 36.25 Hz), 123.9 (q, JCF = 235.0 Hz), 122.3, 121.1
(q, 3JCF = 6.25 Hz), 118.3, 116.8, 83.0, 54.7; HRMS (ESI/QTOF) m/
z [M + H]+ calcd for C19H11F6N2O4 445.0618, found 445.0618.
Ethyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]quinazoline-
12-carboxylate (Scheme 2, 2i). Orange solid (0.0933 g, 85%
1
yield); mp 240−242 °C; Rf 0.34 (40% EtOAc/hexanes); H NMR
(500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.74
(t, J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.55−7.51 (m, 2H),
7.48−7.44 (m, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H),
4.21−4.08 (m, 2H), 1.02 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125
MHz, DMSO-d6) δ 184.5, 168.9, 149.7, 144.1, 140.1, 138.6, 131.2,
129.5, 128.9, 126.9, 126.1, 125.3, 124.0, 120.1, 113.2, 82.6, 62.9, 14.2;
HRMS (ESI/QTOF) m/z [M + H]+ calcd for C18H15N2O4 323.1026,
found 323.1028.
Methyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
quinazoline-12-carboxylate (Scheme 2, 2a). Orange solid (0.0932
1
g, 89% yield); mp 240−242 °C; Rf 0.34 (40% EtOAc/hexanes); H
NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H),
7.74 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.57−7.45 (m, 3H),
7.24 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 3.68 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 184.4, 169.5, 149.5, 144.0,
Butyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]quinazoline-
12-carboxylate (Scheme 2, 2j). Red solid (0.0836 g, 70% yield);
mp 171−173 °C; Rf 0.42 (30% EtOAc/hexanes); 1H NMR (400
MHz, CDCl3) δ 7.69 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H),
7.51 (dd, J = 7.6, 1.6 Hz, 1H), 7.43−7.40 (m, 1H), 7.33−7.21 (m,
2H), 7.18−7.14 (m, 2H), 5.84 (s, 1H), 4.20−4.06 (m, 2H), 1.41−
1.34 (m, 2H), 0.99−0.89 (m, 2H), 0.65 (t, J = 7.2 Hz, 4H); 13C{1H}
NMR (100 MHz, CDCl3) δ 183.5, 169.6, 149.0, 143.9, 139.4, 137.6,
130.9, 129.1, 128.9, 126.0, 125.4, 124.2, 123.7, 120.3, 112.4, 82.0,
67.5, 30.0, 18.5, 13.3; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C20H19N2O4 351.1339, found 351.1340.
Benzyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]quinazoline-
12-carboxylate (Scheme 2, 2k). Orange solid (0.1031 g, 79% yield);
mp 175−177 °C; Rf 0.32 (30% EtOAc/hexanes); 1H NMR (400
MHz, DMSO-d6) δ 8.22 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.65−7.49
(m, 5H), 7.45−7.42 (m, 1H), 7.26−7.17 (m, 5H), 7.05 (d, J = 7.6 Hz,
2H), 5.19 (d, J = 12.4 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 189.2, 173.4, 154.3, 148.9, 144.9,
143.3, 140.3, 136.1, 134.2, 133.7, 133.5, 133.4, 132.9, 131.7, 130.7,
130.0, 128.8, 128.0, 124.8, 118.1, 117.4, 87.6, 72.7; HRMS (ESI/
QTOF) m/z [M + H]+ calcd for C23H17N2O4 385.1183, found
385.1185.
140.0, 138.7, 131.3, 129.5, 128.9, 126.9, 125.9, 125.3, 124.0, 120.1,
113.1, 82.5, 54.1; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C17H13N2O4 309.0870, found 309.0870.
Methyl 12-Hydroxy-2,8-dimethyl-6-oxo-6,12-dihydroindolo[2,1-
b]quinazoline-12-carboxylate (Scheme 2, 2b). Yellow solid (0.093
1
g, 81% yield); mp 229−230 °C; Rf 0.36 (30% EtOAc/hexanes); H
NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 7.37 (d, J = 8.5 Hz, 2H),
7.27 (s, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz,1H), 5.44
(s, 1H), 3.72 (s, 3H), 2.37 (s, 6H); 13C{1H} NMR (125 MHz,
CDCl3) δ 183.7, 170.6, 146.9, 143.6, 139.6, 138.2, 137.3, 133.5, 131.9,
129.0, 126.3, 125.5,123.8, 120.6, 111.8, 81.9, 54.4, 21.4, 20.8; HRMS
(ESI/QTOF) m/z [M + H]+ calcd for C19H17N2O4 337.1183, found
337.1184.
Methyl 12-Hydroxy-2,8-dimethoxy-6-oxo-6,12-dihydroindolo-
[2,1-b]quinazoline-12-carboxylate (Scheme 2, 2c). Red oil
(0.1089 g, 87% yield); Rf 0.31 (30% EtOAc/hexanes); 1H NMR
(500 MHz, CDCl3) δ 7.41 (d, J = 8.5 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J
= 8.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.98 (s, 1H), 6.84 (d, J = 8.5
Hz,1H), 5.44 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.72 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 183.6, 170.4, 160.3, 156.3,
4-Methoxybenzyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
143.2, 133.3, 130.6, 125.4, 125.0,121.3, 117.0, 113.2, 110.7, 108.3,
82.1, 55.9, 55.8, 54.4; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C19H17N2O6 369.1081, found 369.1082.
quinazoline-12-carboxylate (Scheme 2, 2l). Orange solid (0.1211
1
g, 86% yield); mp 178−181 °C Rf 0.37 (30% EtOAc/hexanes); H
NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H),
7.64−7.53 (m, 4H), 7.45−7.41 (m, 1H), 7.21 (t, J = 7.2 Hz, 1H),
7.12 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz,
2H), 5.14 (d, J = 12.0 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 3.72 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 184.4, 168.7, 159.7,
149.5, 144.1, 140.1, 138.5, 131.2, 130.3, 129.4, 128.9, 127.4, 126.9,
126.0, 125.2, 123.9, 120.0, 114.1, 113.2, 82.7, 67.9, 55.5; HRMS
(ESI/QTOF) m/z [M + H]+ calcd for C24H19N2O5 415.1288, found
415.1289.
Methyl 2,8-Dibromo-12-hydroxy-6-oxo-6,12-dihydroindolo[2,1-
b]quinazoline-12-carboxylate (Scheme 2, 2d). Orange solid
(0.0901 g, 57% yield); mp 259−260 °C; Rf 0.32 (40% EtOAc/
hexanes); 1H NMR (500 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.94 (d, J
= 2.0 Hz, 1H), 7.91 (dd, J = 8.5, 2.0 Hz, 1H), 7.74 (dd, J = 8.5, 2.5
Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.19 (d, J
= 8.5 Hz, 1H), 3.69 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ
182.9, 168.8, 148.1, 144.0, 140.7, 139.3, 134.4, 130.9, 129.5, 127.79,
127.71, 121.93, 121.90, 116.2, 115.4, 82.3, 54.4; HRMS (ESI/QTOF)
m/z [M + H]+ calcd for C17H1179Br2N2O4 464.9080, found 464.9076,
calcd for C17H1181Br2N2O4 468.9040, found 468.9039.
4-Isopropylbenzyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
quinazoline-12-carboxylate (Scheme 2, 2m). Orange solid (0.1145
1
g, 79% yield); mp 190−192 °C; Rf 0.36 (30% EtOAc/hexanes); H
Methyl 2,8-Dichloro-12-hydroxy-6-oxo-6,12-dihydroindolo[2,1-
b]quinazoline-12-carboxylate (Scheme 2, 2e). Orange solid
(0.0425 g, 33% yield); mp 257−258 °C; Rf 0.35 (30% EtOAc/
NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H),
7.61 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 2.8 Hz, 2H), 7.46−7.42 (m,
1H), 7.21 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0
Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 5.17 (d, J = 12.4 Hz, 1H), 5.08 (d,
J = 12.4 Hz, 1H), 2.83 (sep, J = 7.2 Hz, 1H), 1.16 (d, J = 7.2 Hz, 6H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 184.4, 168.7, 149.6, 149.0,
144.1, 140.1, 138.5, 132.9, 131.3, 129.5, 128.9, 128.4, 127.0, 126.7,
126.0, 125.2, 124.0, 120.1, 113.3, 82.8, 68.0, 33.6, 24.3, 24.2; HRMS
(ESI/QTOF) m/z [M + H]+ calcd for C26H23N2O4 427.1652, found
427.1654.
1
hexanes); H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 2.0 Hz, 1H),
7.59 (d, J = 2.5 Hz, 1H), 7.57−7.53 (m, 2H), 7.42 (dd, J = 8.5, 2.5
Hz, 1H), 7.30 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 3.75 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 169.1, 147.4, 138.2, 137.3,
134.9, 131.3, 130.3, 129.7, 126.3, 125.2, 121.4, 113.9, 54.3; HRMS
(ESI/QTOF) m/z [M + H]+ calcd for C17H1135Cl2N2O4 377.0090,
found 377.0091, calcd for C17H1137Cl2N2O4 381.0030, found
381.0034.
E
https://dx.doi.org/10.1021/acs.joc.0c02403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
4-Chlorobenzyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
(ESI/QTOF) m/z [M + H]+ calcd for C19H17N2O4 337.1183, found
337.1184.
quinazoline-12-carboxylate (Scheme 2, 2n). Orange solid (0.0821
1
g, 75% yield); mp 212−215 °C; Rf 0.34 (30% EtOAc/hexanes); H
Quinolin-8-yl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
quinazoline-12-carboxylate (Scheme 2, 2u). Orange solid (0.0818
NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.75 (dd, J = 8.0, 1.2 Hz,
1H), 7.62 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6
Hz, 2H), 7.47−7.42 (m, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.22 (t, J = 7.6
Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 5.21 (d, J
= 12.4 Hz, 1H), 5.12 (d, J = 12.4 Hz, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 184.4, 168.6, 149.5, 144.1, 140.1, 138.5, 134.5, 133.4,
131.3, 130.2, 129.5, 128.9, 128.8, 126.9, 125.9, 125.3, 124.0, 120.1,
113.2, 82.8, 67.2; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C23H1635ClN2O4 419.0793, found 419.0793, calcd for
C23H1637ClN2O4 421.0763, found 421.0766.
1
g, 57% yield); mp 236−237 °C; Rf 0.35 (30% EtOAc/hexanes); H
NMR (500 MHz, CDCl3) δ 9.16 (dd, J = 4.2, 1.5 Hz, 1H), 8.30 (dd, J
= 8.5, 1.5 Hz, 1H), 7.80 (ddd, J = 7.5, 1.2, 1.0 Hz, 1H), 7.75 (d, J =
7.5, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 8.5, 4.5 Hz, 1H),
7.44−7.40 (m, 2H), 7.29−7.25 (m, 2H), 7.18 (td, J = 7.5, 1.2 Hz,
1H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 6.74 (dd, J = 8.0, 1.5 Hz, 1H),
6.27 (d, J = 8.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 183.2,
172.0, 152.3, 148.7, 148.4, 144.3, 139.0, 137.9, 136.7, 134.9, 131.0,
130.8, 130.6, 129.8, 126.6, 126.4, 125.9, 125.7, 123.8, 123.4, 121.3,
120.7, 110.3, 65.4; HRMS (ESI/QTOF) m/z [M−OH]+ calcd for
C25H14N3O3 404.1030, found 404.1030.
4-Nitrobenzyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
quinazoline-12-carboxylate (Scheme 2, 2o). Orange solid (0.0817
1
g, 56% yield); mp 205−207 °C; Rf 0.30 (40% EtOAc/hexanes); H
4-Allyl-2-methoxyphenyl 12-Hydroxy-6-oxo-6,12-dihydroindolo-
[2,1-b]quinazoline-12-carbo-xylate (Scheme 2, 2v). Orange solid
(0.0466 g, 31% yield); mp 236−237 °C; Rf 0.42 (30% EtOAc/
hexanes); 1H NMR (500 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.84 (td, J
= 8.0, 2.0 Hz, 1H), 7.81−7.78 (m, 2H), 7.61−7.54 (m, 3H), 7.44 (d, J
= 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.79
(d, J = 8.0 Hz, 1H), 6.72 (dd, J = 8.0, 2.0 Hz, 1H), 5.97−5.89 (m,
1H), 5.09−5.03 (m, 2H), 3.52 (s, 3H), 3.33 (d, J = 7.0 Hz, 2H);
13C{1H} NMR (125 MHz, DMSO-d6) δ 184.4, 167.1, 150.7, 149.5,
144.0, 140.1, 138.4, 137.7, 137.4, 131.4, 129.5, 129.0, 127.3, 125.7,
125.2, 124.1, 122.1, 120.8, 120.2, 116.6, 113.8, 113.6, 82.7, 55.9, 40.3;
HRMS (ESI/QTOF) m/z [M + H]+ calcd for C26H21N2O5 441.1445,
found 441.1446.
NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H),
7.77 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz,
1H), 7.56 (s, 2H), 7.49−7.46 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.22
(t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 5.35 (d, J = 13.5 Hz,
1H), 5.27 (d, J = 13.5 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 184.3, 168.5, 149.5, 147.6, 144.2, 143.1, 140.1, 138.5, 131.4,
129.6, 129.1, 129.0, 127.0, 125.8, 125.3, 124.0, 123.8, 120.1, 113.3,
82.8, 66.7; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C23H16N3O6 430.1034, found 430.1034.
3-Phenoxybenzyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
quinazoline-12-carboxylate (Scheme 2, 2p). Orange oil (0.1228 g,
1
76% yield); Rf 0.36 (30% EtOAc/hexanes); H NMR (400 MHz,
DMSO-d6) δ 8.25 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.64−7.56 (m,
2H), 7.55−7.50 (m, 2H), 7.41−7.35 (m, 3H), 7.24 (t, J = 8.0 Hz,
1H), 7.21−7.13 (m, 3H), 6.93−6.84 (m, 3H), 6.73 (s, 1H), 5.19 (d, J
= 12.8 Hz, 1H), 5.12 (d, J = 12.8 Hz, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 184.4, 168.6, 156.9, 156.8, 149.5, 144.1, 140.1, 138.9,
138.5, 137.7, 131.3, 130, 129.4, 128.9, 126.9, 125.8, 125.3, 124.0,
123.2, 120.1, 119.0, 118.9, 118.4, 113.2, 82.8, 67.5; HRMS (ESI/
QTOF) m/z [M + H]+ calcd for C29H21N2O5 477.1445, found
477.1446.
(E)-3,7-Dimethylocta-2,6-dien-1-yl 12-Hydroxy-6-oxo-6,12-
dihydroindolo[2,1-b]quinazoline-12-carboxylate (Scheme 2, 2w).
Yellow solid (0.1037 g, 71% yield); mp 104−105 °C; Rf 0.32 (30%
1
EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.74 (dd, J = 7.5,
1.2 Hz, 1H), 7.57−7.54 (m, 2H), 7.46−7.44 (m, 1H), 7.37−7.31 (m,
2H), 7.16 (td, J = 7.5, 1.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.39 (s,
1H), 5.09−5.06 (m, 1H), 4.99−4.95 (m, 1H), 4.69 (dd, J = 12.0, 7.2
Hz, 1H), 4.58 (dd, J = 12.0, 7.2 Hz, 1H), 1.94−1.89 (m, 2H), 1.87−
1.83 (m, 2H), 1.65 (d, J = 1.0 Hz, 3H), 1.55 (s, 3H), 1.45 (d, J = 1.0
Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 183.7, 170.0, 148.9,
145.3, 143.8, 139.6, 137.4, 132.0, 130.9, 129.2, 129.0, 125.8, 125.4,
124.2, 123.7, 123.4, 120.4, 116.2, 112.3, 81.9, 64.5, 39.3, 26.1, 25.7,
17.7, 16.4; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C26H27N2O4 431.1965, found 431.1966.
General Procedure for the Synthesis of Tryptanthrins 3. To a
solution of iodine (129 mg, 0.51 mmol) and triphenylphosphine (134
mg, 0.51 mmol) in freshly distilled dichloromethane (5 mL) were
added isatins (0.68 mmol), followed by triethylamine (0.24 mL, 1.70
mmol) at 0 °C under N2. The reaction mixture was allowed to warm
up to room temperature with continuous stirring. After completion of
the reaction, the crude mixture was concentrated under reduced
pressure before purification by column chromatography (CC) using
ethyl acetate/hexanes as the eluent. Gram scale synthesis of 3a was
carried out as described above using 1a (1.47 g, 10 mmol), iodine (1.9
g, 7.5 mmol), triphenylphosphine (1.97 g, 7.5 mmol), and
triethylamine (3.5 mL, 25 mmol) in freshly distilled dichloromethane
(50 mL) to yield 3a in 0.8815 g (71%).
Cinnamyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
quinazoline-12-carboxylate (Scheme 2, 2q). Yellow solid (0.0921
1
g, 66% yield); mp 197−198 °C; Rf 0.30 (30% EtOAc/hexanes; H
NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.77 (d, J = 7.5 Hz, 1H),
7.68 (t, J = 7.0 Hz, 2H), 7.58−7.53 (m, 2H), 7.49−7.45 (m, 1H),
7.34−7.26 (m, 6H), 7.21 (t, J = 7.5 Hz, 1H), 6.37 (d, J = 16.0 Hz,
1H), 6.18 (dt, J = 16.0, 5.8 Hz, 1H), 4.80 (m, 2H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 184.5, 168.6, 149.6, 144.1, 140.1, 138.5,
136.0, 133.5, 131.3, 129.5, 129.1, 129.0, 128.6, 127.0, 126.9, 126.0,
125.3, 124.0, 123.0, 120.1, 113.3, 82.7, 66.6; HRMS (ESI/QTOF) m/
z [M + H]+ calcd for C25H19N2O4 411.1339, found 411.1335.
Cyclohexyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
quinazoline-12-carboxylate (Scheme 2, 2r). Orange oil (0.0832 g,
1
65% yield); Rf 0.36 (30% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) δ 7.76 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 7.5, 1.5 Hz, 1H),
7.57 (td, J = 7.5, 1.5 Hz, 1H), 7.46 (dd, J = 7.5, 1.5 Hz, 1H), 7.39 (td,
J = 7.5, 1.5 Hz, 1H), 7.34 (td, J = 7.5, 1.5 Hz, 1H), 7.17 (t, J = 7.5 Hz,
1H), 7.15 (d, J = 7.5 Hz, 1H), 4.87−4.82 (m, 1H), 1.60−1.52 (m,
2H), 1.38−1.33 (m, 3H), 1.25−1.09 (m, 5H); 13C NMR (125 MHz,
CDCl3) δ 183.9, 169.5, 149.1, 144.0, 139.7, 137.5, 130.9, 129.3, 129.1,
125.52, 125.49, 124.4, 123.8, 120.5, 112.2, 82.0, 76.9, 30.8, 30.6, 24.8,
22.9; HRMS (ESI/QTOF) m/z [M + H]+ calcd for C22H21N2O4
377.1496, found 377.1498.
Indolo[2,1-b]quinazoline-6,12-dione (Tryptanthrin) (Scheme 3,
3a). Yellow solid (0.0667 g, 79% yield); mp 259−260 °C (lit.14a mp
1
260−262 °C); Rf 0.36 (20% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) δ 8.62 (d, J = 8.5 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.03 (d, J
= 8.0 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.79
(t, J = 8.0 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 182.6, 158.1, 146.6, 146.4,
Isopropyl 12-Hydroxy-6-oxo-6,12-dihydroindolo[2,1-b]-
quinazoline-12-carboxylate (Scheme 2, 2s). Orange solid (0.0607
1
g, 53% yield); mp 205−207 °C; Rf 0.34 (30% EtOAc/hexanes); H
144.3, 138.3, 135.2, 130.7, 130.3, 127.6, 127.2, 125.4, 123.8, 121.9,
118.0.
2,8-Dimethylindolo[2,1-b]quinazoline-6,12-dione (Scheme 3,
3b). Yellow solid (0.0752 g, 80% yield); mp 248−250 °C (lit.11b
mp 249.8−251.6 °C); Rf 0.40 (20% EtOAc/hexanes); 1H NMR (500
MHz, CDCl3) δ 8.48 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H),
7.90 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.0,
NMR (500 MHz, CDCl3) δ 7.74 (d, J = 7.5 Hz, 1H), 7.59−7.54 (m,
2H), 7.49−7.45 (m, 1H), 7.37−7.31 (m, 2H), 7.16 (t, J = 7.5 Hz,
1H), 7.14 (d, J = 7.5 Hz, 1H), 5.06 (sep, J = 6.5 Hz, 1H), 1.06 (d, J =
6.5 Hz, 2H), 1.01 (d, J = 6.5 Hz, 2H); 13C{1H} NMR (125 MHz,
CDCl3) δ 183.8, 169.5, 149.0, 143.9, 139.6, 137.5, 130.9, 129.2, 129.1,
125.6, 125.5, 124.3, 123.7, 120.4, 112.2, 81.9, 72.4, 21.3, 21.1; HRMS
F
https://dx.doi.org/10.1021/acs.joc.0c02403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
2.0 Hz, 1H), 7.57 (dd, J = 8.0, 2.0 Hz, 1H), 2.55 (s, 3H), 2.45 (s,
3H).
Development of Health Promoting Products from Northern
Resources, Faculty of Science, Chiang Mai University, Chiang
Mai 50200, Thailand; orcid.org/0000-0002-7484-122X
Nittaya Wiriya − Department of Chemistry, Faculty of Science,
Chiang Mai University, Chiang Mai 50200, Thailand
Surat Hongsibsong − School of Health Science Research,
Research Institute for Health Science, Chiang Mai University,
Chiang Mai 50200, Thailand
2,8-Dimethoxyindolo[2,1-b]quinazoline-6,12-dione (Scheme 3,
3c). Yellow solid (0.0883 g, 84% yield); mp 284−285 °C (lit.18 mp
1
285−288 °C); Rf 0.39 (30% EtOAc/hexanes); H NMR (500 MHz,
CDCl3) δ 8.51 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.81 (d, J
= 3.0 Hz, 1H), 7.38 (dd, J = 9.0, 3.0 Hz, 1H), 7.37 (d, J = 3.0 Hz,
1H), 7.30 (dd, J = 9.0, 3.0 Hz, 1H), 3.99 (s, 3H), 3.89 (s, 3H).
2,8-Dibromoindolo[2,1-b]quinazoline-6,12-dione (Scheme 3,
3d). Yellow solid (0.0762 g, 55% yield); mp 317−319 °C (lit.13b
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02403
1
mp 319−320 °C); Rf 0.39 (20% EtOAc/hexanes); H NMR (500
MHz, CDCl3+CD3OD 4 drops) δ 8.50 (d, J = 2.5 Hz, 1H), 8.45 (d, J
= 8.5 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.5, 2.5 Hz,
1H), 7.87 (dd, J = 8.5, 2.0 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H).
2,8-Dichloroindolo[2,1-b]quinazoline-6,12-dione (Scheme 3,
3e). Yellow solid (0.0432 g, 40% yield); mp 288−290 °C (lit.18 mp
Notes
The authors declare no competing financial interest.
1
289−291 °C); Rf 0.39 (20% EtOAc/hexanes); H NMR (500 MHz,
ACKNOWLEDGMENTS
■
CDCl3) δ 8.53 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 7.93 (d, J
= 8.5 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.5, 2.5 Hz,
1H), 7.73 (dd, J = 8.5, 2.0 Hz, 1H).
This work is partially supported by Chiang Mai University,
Thailand and The Thailand Research Fund through the Royal
Golden Jubilee Ph.D. Program (Grant No. PHD/0072/2559
to N.W.).
3,9-Bis(trifluoromethyl)indolo[2,1-b]quinazoline-6,12-dione
(Scheme 3, 3h). Orange solid (0.0744 g, 57% yield); mp 240−242
1
°C; Rf 0.34 (40% EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ
9.03 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz,
1H), 7.96 (t, J = 8.0 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0
Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 179.6, 167.8, 149.8,
REFERENCES
■
(1) (a) Jao, C.-W.; Lin, W.-C.; Wu, Y.-T.; Wu, P.-L. Isolation,
Structure Elucidation, and Synthesis of Cytotoxic Tryptanthrin
Analogues from Phaius mishmensis. J. Nat. Prod. 2008, 71, 1275.
(b) Chang, C.-F.; Hsu, Y.-L.; Lee, C.-Y.; Wu, C.-H.; Wu, Y.-C.;
Chuang, T.-H. Isolation and cytotoxicity evaluation of the chemical
constituents from Cephalantheropsis gracilis. Int. J. Mol. Sci. 2015, 16,
3980. (c) Jao, C.-W.; Hung, T.-H.; Chang, C.-F.; Chuang, T.-H.
Chemical constituents of Phaius mishmensis. Molecules 2016, 21, 1605.
(d) Kaur, R.; Manjal, S. K.; Rawal, R. K.; Kumar, K. Recent synthetic
and medicinal perspectives of tryptanthrin. Bioorg. Med. Chem. 2017,
25, 4533.
3
142.08, 142.02, 137.2, 134.1, 130.9, 128.7 (q, JCF = 6.25 Hz), 128.0
(q, 2JCF = 33.75 Hz), 122.9 (q, 1JCF = 233.75 Hz), 122.3, 121.1 (q, 3JCF
= 6.25 Hz), 118.3, 116.8, 83.0, 54.7; HRMS (ESI/QTOF) m/z [M +
H]+ calcd for C17H7F6N2O2 385.0406, found 385.0407.
Synthesis of Methyl 12-Methoxy-6-oxo-6,12-dihydroindolo[2,1-
b]quinazoline-12-carboxylate (Cephalanthrine B, Scheme 4, 4). To
a solution of 2a (105 mg, 0.34 mmol) in anhydrous DMF (3 mL)
were added iodomethane (42 μL, 0.68 mmol) and potassium
carbonate (94 mg, 0.68 mmol) at 0 °C. After warming up to room
temperature, the reaction mixture was stirred for 2 h. The crude
mixture was filtered washed with ethyl acetate. The organic layer was
concentrated under reduced pressure before purification by column
chromatography (CC) using ethyl acetate/hexanes as the eluent to
provide compound 4 as a yellow solid (0.0898 g, 82% yield); mp
214−216 °C (lit.1b mp 215−217 °C); Rf 0.41 (20% EtOAc/hexanes);
1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 7.5 Hz, 1H), 7.72 (d, J =
8.0 Hz, 1H), 7.63−7.59 (m, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.42 (t, J =
7.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 3.71
(s, 3H), 3.07 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 184.0,
167.8, 148.9, 144.7, 141.9, 138.0, 131.5, 129.7, 129.4, 126.1, 125.5,
124.0, 120.5, 120.3, 112.3, 87.4, 53.8, 50.6.
(2) (a) Michael, J. P. Quinoline, quinazoline, and acridone alkaloids.
Nat. Prod. Rep. 2007, 24, 223. (b) Jahng, Y. Progress in the studies on
tryptanthrin, an alkaloid of history. Arch. Pharmacal Res. 2013, 36,
517.
(3) (a) Yang, S.; Li, X.; Hu, F.; Li, Y.; Yang, Y.; Yan, J.; Kuang, C.;
Yang, Q. Discovery of Tryptanthrin Derivatives as Potent Inhibitors of
Indoleamine 2,3-Dioxygenase with Therapeutic Activity in Lewis
Lung Cancer (LLC) Tumor-Bearing Mice. J. Med. Chem. 2013, 56,
8321. (b) Yang, D.; Zhang, S.; Fang, X.; Guo, L.; Hu, N.; Guo, Z.; Li,
X.; Yang, S.; He, J. C.; Kuang, C.; Yang, Q. N-Benzyl/Aryl Substituted
Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and
Tryptophan 2,3-Dioxygenase. J. Med. Chem. 2019, 62, 9161. (c) Jun,
K.-Y.; Park, S.-E.; Liang, J. L.; Jahng, Y.; Kwon, Y. Benzo[b]-
tryptanthrin Inhibits MDR1, Topoisomerase Activity, and Reverses
Adriamycin Resistance in Breast Cancer Cells. ChemMedChem 2015,
10, 827.
(4) (a) Krivogorsky, B.; Grundt, P.; Yolken, R.; Jones-Brando, L.
Inhibition of Toxoplasma gondii by indirubin and tryptanthrin
analogs. Antimicrob. Agents Chemother. 2008, 52, 4466. (b) Scovill, J.;
Blank, E.; Konnick, M.; Nenortas, E.; Shapiro, T. Antitrypanosomal
activities of tryptanthrins. Antimicrob. Agents Chemother. 2002, 46,
882.
(5) (a) Bandekar, P. P.; Roopnarine, K. A.; Parekh, V. J.; Mitchell, T.
R.; Novak, M. J.; Sinden, R. R. Antimicrobial Activity of Tryptanthrins
in Escherichia coli. J. Med. Chem. 2010, 53, 3558. (b) Kamal, A.;
Reddy, B. V. S.; Sridevi, B.; Ravikumar, A.; Venkateswarlu, A.;
Sravanthi, G.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D. Synthesis and
biological evaluation of phaitanthrin congeners as anti-mycobacterial
agents. Bioorg. Med. Chem. Lett. 2015, 25, 3867.
(6) (a) Schepetkin, I. A.; Khlebnikov, A. I.; Potapov, A. S.;
Kovrizhina, A. R.; Matveevskaya, V. V.; Belyanin, M. L.; Atochin, D.
N.; Zanoza, S. O.; Gaidarzhy, N. M.; Lyakhov, S. A.; Kirpotina, L. N.;
Quinn, M. T. Synthesis, biological evaluation, and molecular
modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02403.
1
Copies of H NMR, 13C{1H} NMR spectra of all new
products, optimization data, and 31P{1H} NMR reaction
monitoring study (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wong Phakhodee − Department of Chemistry, Faculty of
Science and Research Center on Chemistry for Development
of Health Promoting Products from Northern Resources,
Faculty of Science, Chiang Mai University, Chiang Mai
50200, Thailand; orcid.org/0000-0002-5489-9555;
Email: wongp2577@gmail.com; Fax: (+) 66-53-892277
Authors
Mookda Pattarawarapan − Department of Chemistry, Faculty
of Science and Research Center on Chemistry for
G
https://dx.doi.org/10.1021/acs.joc.0c02403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors. Eur. J.
Med. Chem. 2019, 161, 179. (b) Lee, S.; Kim, D.-C.; Baek, H. Y.; Lee,
K.-D.; Kim, Y.-C.; Oh, H. Anti-neuroinflammatory effects of
tryptanthrin from Polygonum tinctorium Lour. in lipopolysaccharide-
stimulated BV2 microglial cells. Arch. Pharmacal Res. 2018, 41, 419.
(c) Hamburger, M. Isatis tinctoria - from the rediscovery of an ancient
medicinal plant towards a novel anti-inflammatory phytopharmaceut-
ical. Phytochem. Rev. 2002, 1, 333.
(7) Bhattacharjee, A. K.; Hartell, M. G.; Nichols, D. A.; Hicks, R. P.;
Stanton, B.; Van Hamont, J. E.; Milhous, W. K. Structure-activity
relationship study of antimalarial indolo[2,1-b]quinazoline-6,12-
diones (tryptanthrins). Three dimensional pharmacophore modeling
and identification of new antimalarial candidates. Eur. J. Med. Chem.
2004, 39, 59.
(8) Mani, J. S.; Johnson, J. B.; Steel, J. C.; Broszczak, D. A.; Neilsen,
P. M.; Walsh, K. B.; Naiker, M. Natural product-derived
phytochemicals as potential agents against coronaviruses: A review.
Virus Res. 2020, 284, 197989.
(9) (a) Hwang, J.-M.; Oh, T.; Kaneko, T.; Upton, A. M.; Franzblau,
S. G.; Ma, Z.; Cho, S.-N.; Kim, P. Design, Synthesis, and Structure-
Activity Relationship Studies of Tryptanthrins As Antitubercular
Agents. J. Nat. Prod. 2013, 76, 354. (b) Mitscher, L. A.; Baker, W.
Tuberculosis: a search for novel therapy starting with natural
products. Med. Res. Rev. 1998, 18, 363. (c) Mitscher, L. A.; Baker,
W. R. A search for novel chemotherapy against tuberculosis amongst
natural products. Pure Appl. Chem. 1998, 70, 365.
Photochemical Condensation of Indoles and Anthranilic Acids with
Visible Light and O2. Org. Lett. 2016, 18, 5744.
(18) Wang, C.; Zhang, L.; Ren, A.; Lu, P.; Wang, Y. Cu-Catalyzed
Synthesis of Tryptanthrin Derivatives from Substituted Indoles. Org.
Lett. 2013, 15, 2982.
(19) (a) Gahtory, D.; Chouhan, M.; Sharma, R.; Nair, V. A. Total
Synthesis of a Pyrroloindoloquinazoline Alkaloid. Org. Lett. 2013, 15,
3942. (b) Gao, H.; Luo, Z.; Ge, P.; He, J.; Zhou, F.; Zheng, P.; Jiang,
J. Direct Catalytic Asymmetric Synthesis of β-Hydroxy Acids from
Malonic Acid. Org. Lett. 2015, 17, 5962. (c) Kang, G.; Luo, Z.; Liu,
C.; Gao, H.; Wu, Q.; Wu, H.; Jiang, J. Amino Acid Salts Catalyzed
Asymmetric Aldol Reaction of Tryptanthrin: A Straightforward
Synthesis of Phaitanthrin A and Its Derivatives. Org. Lett. 2013, 15,
4738. (d) Liao, H.; Peng, X.; Hu, D.; Xu, X.; Huang, P.; Liu, Q.; Liu,
L. CoCl2-promoted TEMPO oxidative homocoupling of indoles:
access to tryptanthrin derivatives. Org. Biomol. Chem. 2018, 16, 5699.
(e) Vaidya, S. D.; Argade, N. P. Aryne Insertion Reactions Leading to
Bioactive Fused Quinazolinones: Diastereoselective Total Synthesis of
Cruciferane. Org. Lett. 2013, 15, 4006. (f) Yavari, I.; Solgi, R.; Khajeh-
Khezri, A.; Askarian-Amiri, M.; Halvagar, M. R. Synthesis of
spiroindolo[2,1-b]quinazolines from Huisgen zwitterions and tryptan-
thrin-malononitrile adducts. J. Heterocycl. Chem. 2019, 56, 3396.
(20) (a) Bird, C. W. Structure of methylisatoid. Tetrahedron 1963,
19, 901. (b) Cornforth, J. W. Structures of isamic acid and
methylisatoid. J. Chem. Soc., Perkin Trans. 1 1976, 2004. (c) Cornforth,
S. J.; Hitchcock, P. B.; Rozos, P. Isatin chloride: a phantom. Reactions
of 2-(2,2-dichloro-2,3-dihydro-3-oxoindol-1-yl)-3H-indol-3-one. J.
Chem. Soc., Perkin Trans. 1 1996, 2787. (d) Kimura, N.; Fujita, M.,
Novel Indoloquinazoline compound and method for producing same,
WO2018123467A1, 2018.
(21) (a) Pattarawarapan, M.; Wiriya, N.; Yimklan, S.; Wangngae, S.;
Phakhodee, W. Zwitterionic Ring-Opened Oxyphosphonium Species
from the Ph3P-I2 Mediated Reactions of Benzo[d]oxazol-2(3H)-ones
with Secondary Amines. J. Org. Chem. 2020, 85, 6151. (b) Pattar-
awarapan, M.; Yamano, D.; Wiriya, N.; Phakhodee, W. Metal-Free
Synthesis of 2-N,N-Dialkylaminobenzoxazoles Using Tertiary Amines
as the Nitrogen Source. J. Org. Chem. 2019, 84, 6516. (c) Phakhodee,
W.; Wangngae, S.; Pattarawarapan, M. Approach to the Synthesis of
2,3-Disubstituted-3H-quinazolin-4-ones Mediated by Ph3P-I2. J. Org.
Chem. 2017, 82, 8058. (d) Wangngae, S.; Pattarawarapan, M.;
Phakhodee, W. Ph3P/I2-Mediated Synthesis of N,N′,N″-Substituted
Guanidines and 2-Iminoimidazolin-4-ones from Aryl Isothiocyanates.
J. Org. Chem. 2017, 82, 10331.
(22) (a) Ault, R. G.; Hirst, E. L.; Morton, R. A. Absorption spectra
in relation to the constitution of derivatives of isatin and carbostyril. J.
Chem. Soc. 1935, 1653. (b) Kennewell, P. D.; Miller, D. J.; Scrowston,
R. M.; Westwood, R. Reactions of diazo compounds with isatin and
its derivatives. J. Chem. Res., Synop. 1995, 396. (c) Moriconi, E. J.;
Murray, J. J. Pyrolysis and photolysis of 1-methyl-3-diazooxindole.
Base decomposition of isatin 2-tosylhydrazone. J. Org. Chem. 1964,
29, 3577. (d) Shmidt, M. S.; Perillo, I. A.; Gonzalez, M.; Blanco, M.
M. Reaction of isatin with alkylating agents with acidic methylenes.
Tetrahedron Lett. 2012, 53, 2514.
(23) (a) Netopilova, M.; Houdkova, M.; Urbanova, K.;
Rondevaldova, J.; van Damme, P.; Kokoska, L. In vitro antimicrobial
combinatory effect of Cinnamomum cassia essential oil with 8-
hydroxyquinoline against Staphylococcus aureus in liquid and vapour
phase. J. Appl. Microbiol. 2020, 129, 906. (b) Phopin, K.; Ruankham,
W.; Prachayasittikul, S.; Prachayasittikul, V.; Tantimongcolwat, T.
Insight into the molecular interaction of cloxyquin (5-chloro-8-
hydroxyquinoline) with bovine serum albumin: biophysical analysis
and computational simulation. Int. J. Mol. Sci. 2020, 21, 249. (c) Yin,
X.; Ma, K.; Wang, Y.; Sun, Y.; Shang, X.-F.; Zhao, Z.; Wang, R.; Chen,
Y.; Zhu, J.; Liu, Y.-Q. Design, Synthesis and Antifungal Evaluation of
8-hydroxyquinoline Metal Complexes against Phytopathogenic Fungi.
J. Agric. Food Chem. 2020, 68, 11096.
(10) Tucker, A. M.; Grundt, P. The chemistry of tryptanthrin and its
derivatives. ARKIVOC 2012, 2012, 546.
(11) (a) Sultan, S.; Gupta, V.; Shah, B. A. Photoredox-Catalyzed
Isatin Reactions: Access to Dibenzo-1,7-Naphthyridine Carboxylate
and Tryptanthrin. ChemPhotoChem. 2017, 1, 120. (b) Hou, H.; Li, H.;
Han, Y.; Yan, C. Synthesis of visible-light mediated tryptanthrin
derivatives from isatin and isatoic anhydride under transition metal-
free conditions. Org. Chem. Front. 2018, 5, 51.
(12) Batanero, B.; Barba, F. Electrosynthesis of tryptanthrin.
Tetrahedron Lett. 2006, 47, 8201.
(13) (a) Moskovkina, T. V. New synthesis of 6,12-dihydro-6,12-
dioxoindolo[2,1-b]quinazoline (tryptanthrine, couropitine A). Russ. J.
Org. Chem. 1997, 33, 125. (b) Moskovkina, T. V.; Kalinovskii, A. I.;
Makhan’kov, V. V. Synthesis of tryptanthrin (couroupitine)
derivatives by reaction of substituted isatins with phosphoryl chloride.
Russ. J. Org. Chem. 2012, 48, 123.
(14) (a) Amara, R.; Awad, H.; Chaker, D.; Bentabed-Ababsa, G.;
Lassagne, F.; Erb, W.; Chevallier, F.; Roisnel, T.; Dorcet, V.; Fajloun,
Z.; Vidal, J.; Mongin, F. Conversion of Isatins to Tryptanthrins,
Heterocycles Endowed with a Myriad of Bioactivities. Eur. J. Org.
Chem. 2019, 2019, 5302. (b) Brandao, P.; Pinheiro, D.; Sergio Seixas
de Melo, J.; Pineiro, M. I2/NaH/DMF as oxidant trio for the synthesis
of tryptanthrin from indigo or isatin. Dyes Pigm. 2020, 173, 107935.
(c) Moskovkina, T. V.; Denisenko, M. V.; Kalinovskii, A. I.; Stonik, V.
A. Synthesis of substituted tryptanthrins via oxidation of isatin and its
derivatives. Russ. J. Org. Chem. 2013, 49, 1740. (d) Jia, F.-C.; Zhou,
Z.-W.; Xu, C.; Wu, Y.-D.; Wu, A.-X. Divergent Synthesis of
Quinazolin-4(3H)-ones and Tryptanthrins Enabled by a tert-Butyl
Hydroperoxide/K3PO4-Promoted Oxidative Cyclization of Isatins at
Room Temperature. Org. Lett. 2016, 18, 2942.
(15) (a) Mane, A. H.; Patil, A. D.; Kamat, S. R.; Salunkhe, R. S.
Biocatalyst Mediated Synthesis of Tryptanthrins Performed Under
Ultrasonication. ChemistrySelect 2018, 3, 6454. (b) Kumar, A.;
Tripathi, V. D.; Kumar, P. β-Cyclodextrin catalyzed synthesis of
tryptanthrin in water. Green Chem. 2011, 13, 51. (c) Rai, B.; Shukla,
R. D.; Kumar, A. Zinc oxide-NP catalyzed direct indolation of in situ
generated bioactive tryptanthrin. Green Chem. 2018, 20, 822.
(16) Reddy, B. V. S.; Reddy, D. M.; Reddy, G. N.; Reddy, M. R.;
Reddy, V. K. Domino Oxidative Cyclization of 2-Amino-acetophe-
nones for the One-Pot Synthesis of Tryptanthrin Derivatives. Eur. J.
Org. Chem. 2015, 2015, 8018.
(24) Bezerra, D. P.; Militao, G. C. G.; de Morais, M. C.; de Sousa, D.
P. The dual antioxidant/prooxidant effect of eugenol and its action in
cancer development and treatment. Nutrients 2017, 9, 1367.
(17) Li, X.; Huang, H.; Yu, C.; Zhang, Y.; Li, H.; Wang, W. Synthesis
of Tryptanthrins by Organocatalytic and Substrate Co-catalyzed
H
https://dx.doi.org/10.1021/acs.joc.0c02403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(25) (a) Lei, Y.; Fu, P.; Jun, X.; Cheng, P. Pharmacological
Properties of Geraniol - A Review. Planta Med. 2019, 85, 48. (b) Lira,
M. H. P. d.; Andrade Junior, F. P. d.; Moraes, G. F. Q.; Macena, G. d.
S.; Pereira, F. d. O.; Lima, I. O. Antimicrobial activity of geraniol: an
integrative review. J. Essent. Oil Res. 2020, 32, 187. (c) Maczka, W.;
Winska, K.; Grabarczyk, M. One hundred faces of geraniol. Molecules
2020, 25, 3303.
(26) (a) Vlot, A. H. C.; Aniceto, N.; Menden, M. P.; Ulrich-
Merzenich, G.; Bender, A. Applying synergy metrics to combination
screening data: agreements, disagreements and pitfalls. Drug Discovery
Today 2019, 24, 2286. (b) Bhatia, K.; Bhumika; Das, A.
Combinatorial drug therapy in cancer - New insights. Life Sci. 2020,
258, 118134.
(27) (a) Reddy Panyam, P. K.; Ugale, B.; Gandhi, T. Palladium(II)/
N-Heterocyclic Carbene Catalyzed One-Pot Sequential α-Arylation/
Alkylation: Access to 3,3-Disubstituted Oxindoles. J. Org. Chem. 2018,
83, 7622. (b) Zhang, A.; Yu, M.; Lan, T.; Liu, Z.; Mao, Z. Novel
synthesis of 4- or 6-substituted indirubin derivatives. Synth. Commun.
2010, 40, 3125.
I
https://dx.doi.org/10.1021/acs.joc.0c02403
J. Org. Chem. XXXX, XXX, XXX−XXX